ORGANIC LETTERS
Diastereoselective Access to Nonracemic 2-cis-Substituted and 2,6-cis-Disubstituted Piperidines
2011 Vol. 13, No. 23 6292–6295
Nicolas Coia, Naı¨ma Mokhtari, Jean-Luc Vasse,* and Jan Szymoniak* Institut de Chimie Mol eculaire de Reims, CNRS (UMR 6229) and Universit e de Reims, 51687 Reims Cedex 2, France
[email protected];
[email protected] Received October 18, 2011
ABSTRACT
Access to nonracemic amino ketones via a hydrozirconation/transmetalation/acylation sequence applied to Boc-protected 1-aminobut-3-enes is presented. This method was applied to the stereoselective synthesis of cyclic imines (or iminiums) which were diastereoselectively converted into 2-cis-substituted and 2,6-cis-disubstituted piperidines. The potential of this approach in the field of alkaloid synthesis was illustrated by the synthesis of ()-coniine and ()-indolizidine 209D. Furthermore, access to indolizidines bearing a quaternary center could also be envisioned through this strategy.
Omnipresent in both naturally occurring and biologically active molecules,1 nitrogen-containing heterocycles are crucial synthetic targets. Thus, efforts to develop new (1) (a) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Pergamon Press: New York, 1999; Vol. 13, pp 1161. (b) Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679–3681. (c) Pu, X.; Ma, D. J. Org. Chem. 2003, 68, 4400–4405. (c) Vazzana, I.; Budriesi, R.; Terranova, E.; Ioan, P.; Ugenti, M. P.; Tasso, B.; Chiarini, A.; Sparatore, F. J. Med. Chem. 2007, 50, 334–343. (2) (a) Cossy, J.; Vogel, P. In Studies in Natural Products Chemistry, Part H; Atta-ur-Raman, Ed.; Elsevier: Amsterdam, 1993; Vol. 12, pp 275363. (b) Angle, S. R.; Breittenbucher, J. G. In Studies in Natural Products Chemistry, Part J; Atta-ur-Raman, Ed.; Elsevier: Amsterdam, 1995; Vol. 16, pp 453502. (c) Laschat, S.; Dickner, T. Synthesis 2000, 1791–1813. (d) Guilloteau-Bertin, B.; Comepre, D.; Gil, L.; Marazano, C.; Das, B. C. Eur. J. Org. Chem. 2000, 1391–1399. (e) Weintraub, P. M.; Sabol, J. S.; Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59, 2953–2989. (f) Davis, F. A.; Rao, A.; Carroll, P. J. Org. Lett. 2003, 5, 3855–3857. (g) Fujita, K.; Fujii, T.; Yamaguchi, R. Org. Lett. 2004, 6, 3525–3528. (h) Buffat, M. G. P. Tetrahedron 2004, 60, 1701–1729. (i) Davis, F. A.; Zhang, J.; Li, Y.; Xu, H.; DeBrosse, C. J. Org. Chem. 2005, 70, 5413–5419. (j) Amat, M.; Escolano, C.; Lozano, O.; Gomez-EsqueA.; Griera, R.; Molins, E.; Bosch, J. J. Org. Chem. 2006, 71, 3804–3815. (k) Van Brabandt, W.; Van Landeghem, R.; De Kimpe, N. Org. Lett. 2006, 8, 1105–1108. (l) Fadel, A.; Lahrache, N. J. Org. Chem. 2007, 72, 1780–1784. (m) Lebrun, S.; Couture, A.; Deniau, E.; Grandclaudon, P. Org. Lett. 2007, 9, 2473–2476. (n) No€el, R.; Vanucci-Bacque, C.; Fargeau-Bellassoued, M.-C.; Lhommet, G. Eur. J. Org. Chem. 2007, 476–486. 10.1021/ol202796w r 2011 American Chemical Society Published on Web 11/08/2011
methodologies for building this class of molecules are of continuous interest.2 Classical disconnection implies NC bond-forming condensation or displacement as the ringclosure step. Such a strategy typically involves the prerequisite generation of an electrophilic site onto substrates bearing an amine precursor. Emerging from this approach, crossmetathesis3 and hydroformylation,4 applied to unsaturated amines, allow a general access to several N-heterocycles. We have previously described the preparation of 2substituted pyrrolidines via hydrozirconation of homoallylic amines. The resulting zirconocenes I are subsequently converted into the corresponding iodo intermediates II, (3) (a) Liu, H.; Su, D.; Cheng, G.; Xu, J.; Wang, X; Hu, Y. Org. Biomol. Chem. 2010, 8, 1899–1904. (b) Bates, R. W.; Lu, Y. J. Org. Chem. 2009, 74, 9460–9465. (4) (a) Airiau, E.; Spangenberg, T.; Girard, N.; Schoenfelder, A.; Salvadori, J.; Taddei, M.; Mann, A. Chem.;Eur. J. 2008, 14, 10938– 10948. (b) Spangenberg, T.; Breit, B.; Mann, A. Org. Lett. 2009, 11, 261– 264. (c) Airiau, E.; Girard, N.; Mann, A.; Salvadori, J.; Taddei, M. Org. Lett. 2009, 11, 5314–5317. (d) Airiau, E.; Spangenberg, T.; Girard, N.; Breit, B.; Mann, A. Org. Lett. 2010, 12, 528–531. (e) Arena, G.; Zill, N.; Salvadori, J.; Girard, N.; Mann, A.; Taddei, M. Org. Lett. 2011, 13, 2294–2297. (5) (a) Ahari, M.; Joosten, A.; Vasse, J.-L.; Szymoniak, J. Synthesis 2008, 61–68. (b) Delaye, P.-O.; Pradhan, T. K.; Lambert, E.; Vasse, J.-L.; Szymoniak, J. Eur. J. Org. Chem. 2010, 3395–3406.
which spontaneously cyclize to afford the pyrrolidines (Scheme 1).5
Scheme 1. Hydrozirconation/Iodination-Mediated Synthesis of Pyrrolidines
When considering the aminozirconocene I involved in the above strategy, one may distinguish a bis-nucleophilic entity, opening the way to coupling with divalent electrophiles (Figure 1). Thus, applied to homoallylic amines, the sequence hydrozirconation/coupling with an acyl chloride would provide an alternative to the Rh-catalyzed hydroacylation.6 In turn, such a strategy would allow an access to substituted piperidines by successive reaction of the C- and the N-poles of a 4-aminobutylzirconocene (Figure 1).
Figure 1. Approach toward piperidines.
In this paper, we present a synthetic methodology that allows the preparation of enantiopure piperidines via a sequential hydrozirconation/acylation followed by an intramolecular reductive amination. The feasibility of the approach was first tested starting from the N-Boc-protected amine 1.7 In that case, a complete hydrozirconation of the substrate was obtained using 1.1 equiv of the Schwartz reagent.
(6) Kim, G.; Lee, E.-j Tetrahedron: Asymmetry 2001, 12, 2073–2076. (7) For the preparation of 1, see the Supporting Information. (8) (a) Carr, D. B.; Schwartz, J. J. Am. Chem. Soc. 1977, 99, 638–640. (b) Zhao, C.; Li, P.; Cao, X.; Xi, Z. Chem.;Eur. J. 2002, 8, 4292–4298. (9) (a) Wipf, P.; Nunes, R. L. Tetrahedron 2004, 60, 1369–1379. (b) Wipf, P.; Pierce, J. G. Org. Lett. 2005, 7, 3537–3740. (c) Wipf, P.; Kendall, C. Chem.;Eur. J. 2002, 8, 1779–1784. (10) (a) Wipf, P. Synthesis 1993, 537–557. (b) Wipf, P.; Takahashi, H. J. Chem. Soc., Chem. Commun. 1996, 2675–2676. (c) Yoshifuji, M.; Loots, M.; Schwartz, J. Tetrahedron Lett. 1997, 15, 1303–1306. (d) Sato, A.; Ito, H.; Yamaguchi, Y.; Taguchi, T. Tetrahedron Lett. 2000, 41, 10239–10243. (e) Doherty, S.; Knight, J. G.; Robins, E. G.; Scanlan, T. H.; Champkin, P. A.; Clegg, W. J. Am. Chem. Soc. 2001, 123, 5110– 5111. (f) Sato, A.; Ito, H.; Okada, M.; Nakamura, Y.; Taguchi, T. Tetrahedron Lett. 2005, 46, 8381–8383. Org. Lett., Vol. 13, No. 23, 2011
Although zirconocenes are easily converted into the corresponding halides, they are inert toward most classical electrophiles. The transmetalation typically to Al,8 Zn,9 or Cu10 is a method of choice to readily form more nucleophilic organometallic species.11 Therefore, benzoyl chloride was added in the presence of a transmetalating agent to perform the acylation. While the use of AlCl3, ZnBr2, or Zn(OTf)2 was unsuccessful, both CuI and CuBr 3 SMe2 afforded the expected product. Acylation of alkylzirconocenes is reported to require a catalytic amount of copper salt, but in our case, best results were obtained with an equimolar loading of CuBr 3 SMe2. Several acyl chlorides have been tested in these optimal conditions, leading to the corresponding amino ketones 2 (Table 1). Finally, Boc-deprotection under standard conditions, followed by reductive amination using NaBH(OAc)3, gave the 2-substituted piperidines 3 with generally good diastereoselectivities.12
Table 1. Synthesis of Piperidines 3
entry
R
2 (yield, %)
3 (yield, %)a
drb
1 2 3 4 5
Ph 2-BrC6H4 n-C3H7 n-C4H9 c-C3H5
2a (71) 2b (70) 2c (56) 2d (62) 2e (53)
3a (69) 3b (53) 3c (69) 3d (78) 3e (69)
13:1 4:1 12:1 16:1 15:1
a Yields refer to the major isomer isolated in the diastereomerically pure form. b Determined by 1H NMR on the crude mixture.
Thus, piperidines 3ae bearing an aryl (entries 1 and 2) or an alkyl group (entries 3 and 4) at the 2-position were obtained in good yield. Most compounds were obtained in a highly diastereoselective manner, except 3b. Nevertheless, all compounds could be isolated in diastereomerically pure form after column chromatography. Good diastereoselectivity in this reaction was previously observed13 and postulated to result from an hydride addition occurring onto the more accessible face of an iminium (11) For zirconocene transmetalation to others metals, see: (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853–12910. (b) Lipshutz, B. H.; Pfeiffer, S. S.; Noson, K.; Tomioka, T. Titanium and Zirconium in Organic Synthesis; Wiley: Weinheim, 2002. (c) Wipf, P.; Kendall, C. Topics in Organometallic Chemistry; Takahashi, T., Ed.; Springer: Berlin, 2004; Vol. 8, p 1. (12) The stereochemistry of 3a was assigned by comparison with known isomers: Fujita, K-I; Fujii, T.; Yamaguchi, R. Org. Lett. 2004, 6, 3525–3528. (13) Adriaenssens, L. V.; Austin, C. A.; Gibson, M.; Smith, D.; Hartley, R. C. Eur. J. Org. Chem. 2006, 4998–5001. (14) Hates, J. F.; Shipman, M.; Twin, H. Chem. Commun. 2001, 1784–1785. (b) Girard, N.; Pouchain, L.; Hurvois, J.-P.; Moinet, C. Synlett 2006, 1679–1682. 6293
that adopts a conformation minimizing the steric interactions.14 Such an approach constitutes a simple access toward enantiomerically pure free piperidines as exemplified by the synthesis of (R)-()-coniine4e,15 obtained by hydrogenolysis16 of 3c (Scheme 2).
Scheme 2. Synthesis of ()-Coniine
To extend the potential of the method, we next turned our attention toward the synthesis of 2,6-disubstituted piperidines. For that purpose, a series of enantiomerically pure N-Boc-protected 2-substituted homoallylic amines 4 were prepared according to a known procedure.17 The hydrozirconation/acylation sequence was next applied to 4 using 2 equiv of the Schwartz reagent, since one is consumed by the NH-carbamate, and 2 equiv of the copper salt.
The sequence appears as quite general to afford diversely cis-2,6-disubstituted piperidines (Table 2).18 Thus, piperidines substituted by two aryl groups (entries 25), an aryl and an aliphatic group (entries 1 and 68), and also two alkyl groups (entry 10) were obtained. Furthermore, access to each enantiomer of 6g was allowed by inverting the order of introduction of the substituents R1 and R2 (entry 7 and 8). Piperidine 6i with a vinyl fragment could also be prepared owing to the selective hydrozirconation of the less substituted CdC double bond (entry 9). The diastereoselectivity observed in the reduction step may be rationalized through an axial hydride addition occurring from a half-chair-like conformation that might be favored when the R1 substituent is located in a pseudoequatorial position (Figure 2).
Figure 2. Plausible origin of the cis-selectivity.
To illustrate the synthetic potential of the method, the synthesis of indolizidine 209D6,19 was achieved. Thus, 6j was subjected to hydrogenolysis under acidic conditions to give the corresponding hydroxy ammonium. The chloro ammonium was then generated with SOCl2, and cyclization was promoted by the addition of K2CO3 to provide the target alkaloid (Scheme 3).
Table 2. Synthesis of Piperidines 6
Scheme 3. Synthesis of Indolizidine 209D entry a
1 2a 3 4 5 6 7c 8 9 10
R1
R2
Ph 2-OMeC6H4 Ph Ph Ph Ph Ph i-Bu (E)-PhCHdCH (CH2)3-OBn
Me Ph Ph 3-ClC6H4 2-BrC6H4 c-C3H5 i-Bu Ph Ph n-C6H13
5 (yield, %) 6b (yield, %) 5a (69) 5b (45) 5c (70) 5d (50) 5e (56) 5f (51%) 5g (72) 5h (63) 5i (56) 5j (47)
6a (72) 6b (73) 6c (77) 6d (87) 6e (81) 6f (88) 6g (73) ent-6g (70) 6i (47) 6j (58)
dr >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 >19:1 6.5:1 4:1 5.5:1
a Racemic material was used as substrate. b Yields refer to the major isomer isolated in the diastereomerically pure form. c CuI was used as the transmetalating agent.
(15) For recent asymmetric synthesis of coniine see:(a) Passarella, D.; Barilli, A.; Belinghieri, F.; Fassi, P; Riva, S.; Sacchetti, Silvani, A.; Danieli, B. Tetrahedron: Asymmetry 2005, 16, 2225–2229. (b) Yamashita, Y.; Mizuki, Y.; Kobayashi, S. Tetrahedron Lett. 2005, 46, 1803–1806. (16) (a) Fujita, K-I; Fujii, T.; Komatsubara, A.; Enoki, Y.; Yamaguchi, R. Heterocycles 2007, 74, 673–682. (b) Fellah, M; Santerem, M; Lhommet, G.; Mouries-Mansuy, V. J. Org. Chem. 2010, 75, 7803–7808. (c) Miao, L.; Di Maggio, S. C.; Shu, M.; Trudell, M. L. Org. Lett. 2009, 11, 1579–1582. (d) Breuning, M.; Steiner, M. Tetrahedron: Asymmetry 2008, 19, 1978– 1983. 6294
Additionally, an extension toward piperidines bearing a quaternary center at the 2-position was initiated. Thus, the (17) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada, T.; Ohfune, Y. J. Org. Chem. 2005, 70, 3464–3471. (18) The cis configuration of 6a was assigned by comparison with the known compound: Katritzky, A. R.; Qiu, G.; Yang, B.; Steel, P. J. J. Org. Chem. 1998, 63, 6699–6703. The stereochemistry of all other compounds was deduced by analogy. (19) For a previous synthesis of indolizidine 209D, see: (a) A˚hman, J.; Somfai, P. Tetrahedron 1995, 51, 9747–9756. (b) Pearson, W. H.; Walavalkar, R.; Schkeryantz, J. M.; Fang, W. K.; Blickensdorf, J. D. J. Am. Chem. Soc. 1993, 115, 10183–10194. (20) The cis configuration was deduced from NOE experiments; see the Supporting Information.
Org. Lett., Vol. 13, No. 23, 2011
addition of allylmagnesium bromide onto the cyclic imine 50 c intermediate was tested as a model experiment. In this case, a high diastereoselectivity was observed, affording the cis piperidine 7,20 isolated in its pure diastereomeric form, in 80% yield starting from 5c. Further cyclization through hydrozirconation/iodination5 provided the indolizidine 8 in 63% yield (Scheme 4).
Scheme 4. Synthesis of Piperidines 8
In summary, applied to protected homoallylic amines, the hydrozirconation/acylation sequence allows access to protected amino ketones, ideal precursors of cyclic imines (or iminiums). The methodology thus consists of the sequential activation of the C- and N-termini of homoallylic amines toward a trivalent electrophile. This approach was applied to the diastereoselective synthesis of 2-cis-substituted and cis-2,6-disubstituted piperidines, opening the way to alkaloid synthesis, as illustrated by the synthesis of ()-coniine and ()-indolizidine 209D. Moreover, an access to piperidines bearing a stereocontrolled quaternary center is exemplified. Acknowledgment. We thank Dr. Jean-Bernard Behr (University of Reims-UMR 6229) for fruiful discussions. Financial support of this work by CNRS and by the Agence Nationale pour la Recherche is gratefully acknowledged. Supporting Information Available. Experimental procedures and characterization of all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 23, 2011
6295
